Neuropeptide Y (NPY)-induced reductions in alcohol intake during continuous access and following alcohol deprivation are not altered by restraint stress in alcohol-preferring (P) rats

Administration of neuropeptide Y (NPY) reduces anxiety-like behavior and alcohol intake in alcohol-preferring rats. The present experiment examined whether the effects of NPY on alcohol drinking are modulated by stress exposure during continuous access or following ethanol deprivation. Female P rats underwent 6 weeks of continuous access to 15% v/v ethanol and water prior to intracerebroventricular (ICV) cannula implantation. Deprived rats underwent two cycles of 5 days of ethanol exposure followed by 2 days of ethanol deprivation, while non-deprived rats had uninterrupted access to ethanol. Stressed rats in both ethanol access groups were exposed to restraint stress for 1 h 4-6 h after ethanol was removed from the deprived group in both cycles. ICV infusions of 5.0 μg NPY or aCSF were administered 48 h following the deprivation/stress procedure, after which ethanol was returned. Rats showed increased ethanol intake following ethanol deprivation compared to non-deprived controls. Food and water intake were increased, while ethanol intake was decreased, in rats infused with NPY. Stress did not increase ethanol intake or alter the response to NPY. Although no stress effects were found, the present experiment replicates previous findings regarding the effectiveness of NPY in reducing ethanol consumption. Future studies aimed at determining the extent to which stress may affect relapse to ethanol drinking and response to NPY would benefit from implementing different stress paradigms and varying the pattern of ethanol access.     

Neuropeptide Y administration into the third ventricle does not increase sucrose or ethanol self-administration but does affect the cortical EEG and increases food intake

RATIONALE: Several studies have provided indirect evidence that neuropeptide Y (NPY) may play a role in the regulation of ethanol consumption. However, the direct effects of central NPY administration on ethanol drinking are unclear. OBJECTIVE: This study examined the effects of NPY on ethanol, sucrose, and food consumption as well as its concomitant effects on the cortical EEG. METHODS: Wistar rats were implanted with cortical recording electrodes and a cannula in the third ventricle after using a sucrose substitution procedure to establish ethanol self-administration. NPY (0-15 microg/3.0 microl) was infused into the third ventricle prior to drinking sessions, when 10% ethanol (10E), 2% sucrose (2S), 0.5% sucrose (0.5S), or food were available. Behavior and cortical EEG were monitored during the sessions. RESULTS: NPY had no effect on the intake of 10E, 2S, or 0.5S, but NPY (15 microg/3.0 microl) significantly increased food intake. Under baseline drinking conditions, EEG power in the 6-8 Hz range was significantly greater when 2S was consumed compared to 10E. NPY decreased power in the 8-16 Hz range, decreased peak frequency in the 6-8 Hz range, and increased peak frequency in the 32-50 Hz range when 10E or 2S was available. CONCLUSIONS: These data suggest that NPY administration into the third ventricle preferentially regulates feeding compared to ethanol or sucrose drinking. In addition, since NPY significantly altered the cortical EEG in the absence of effects on ethanol and sucrose consumption, these data may indicate that NPY's cortical EEG effects are more related to its sedative or anxiolytic properties, rather than any effect on consumption.     

Facilitation of ethanol consumption by intracerebroventricular infusions of corticosterone

Male Wistar rats bearing intracerebroventricular (ICV) cannulae and with simultaneous access to 6% ethanol and water were subjected to adrenalectomy (ADX) or sham surgery. ADX decreased ethanol intake. Starting a few days later, the animals received ICV infusions with 100 μg corticosterone acetate (CORT) with 2-to 3-day intervals for 2 weeks. ICV CORT, but not SC CORT at the same dose, restored ethanol consumption in ADX rats to preoperative levels, whereas vehicle infusions (propylene, glycol) did not. Adrenally intact animals, which normally consumed moderate amounts of ethanol (≈0.5 g/kg per day), also showed a robust effect of ICV infusions of CORT, whereas this facilitatory effect was not observed in high consumers (≈3.0 g/kg per day). The suppressive effect of ADX on ethanol intake was not reproduced by concurrent and repeated ICV infusions of intracellular mineralocorticoid (RU 28318) and glucocorticoid (mifepristone) receptor blockers. It is concluded that CORT stimulates alcohol consumption by acting in the brain, probably by way of neuronal membrane mechanisms.     

Neuropeptide Y (NPY) in the central nucleus of the amygdala (CeA) does not affect ethanol-reinforced responding in binge-drinking, nondependent rats

The central nucleus of the amygdala (CeA) has been implicated as having a significant role in mediating alcohol-drinking behavior. Neuropeptide Y (NPY) has been investigated as a potential pharmacotherapeutic due to its ability to attenuate ethanol intake, particularly when administered into the CeA. Previous research suggests, though the evidence is somewhat conflicting, that the efficacy of NPY is contingent upon genetic background and/or prior history of ethanol dependence in rats. However, studies looking at the effects of NPY in nonselected animals lacking a history of ethanol dependence have two factors that could impact the interpretation of the results: ethanol history/selection AND relatively low baseline ethanol intakes as compared to ethanol-dependent and/or genetically selected controls. The purpose of the present study was to generate higher baseline ethanol intakes upon which to examine the effects of NPY on ethanol and sucrose drinking in nonselected rats using a binge drinking model. Long Evans rats were trained to complete a single response requirement resulting in access to either 2% sucrose (Sucrose Group) or 2% sucrose/10% ethanol (Ethanol Group) for a 20-min drinking session. On treatment days, rats were bilaterally microinjected into the CeA with aCSF or one of three doses of NPY (0.25 μg, 0.50 μg, or 1.00 μg/.5 μL). Subjects in the Ethanol Group were consuming an average of 1.2 g/kg of ethanol (yielding BELs of ~ 90 mg%) during the 20 min access period following aCSF treatments. The results revealed that NPY had no effect on either sucrose or ethanol consumption or on appetitive responding (latency to respond). Overall, the findings indicate that even a history of binge-like ethanol consumption is not sufficient to recruit CeA NPY activity, and are consistent with previous studies showing that the role of NPY in regulating ethanol reinforcement in the CeA may be contingent upon a prior history of ethanol dependence.     

Differential feeding responses evoked in the rat by NPY and NPY1-27 injected intracerebroventricularly

Neuropeptide Y (NPY) given by the intracerebroventricular (ICV) route in the rat evokes hyperphagic-like feeding. To examine the molecular nature of action of NPY, comparisons were made between the central effects of this peptide and a newly synthesized amino-terminus fragment, NPY1-27. A single guide tube was implanted stereotaxically to rest just above a lateral cerebral ventricle so that ICV injections in a volume of 10 microliters of either CSF control vehicle or peptide could be given in the unrestrained rat. Native NPY or NPY1-27 was given in doses of 5.0 or 10.0 micrograms, whereas nondeprotected NPY was infused in a dose of 10.0 micrograms. The intakes of either regular commercial rat diet or specially prepared chocolate-flavored biscuits as well as water were recorded intermittently for 4.0 h following each ICV infusion. Although a clear-cut dose response with a latency of similar magnitude emerged for both molecules, NPY was found to be nearly twice as potent as NPY1-27 in inducing spontaneous feeding. A corresponding infusion in the same volume of either nondeprotected NPY or CSF control vehicle was without effect. When chocolate-flavored biscuits were provided to the rat, an ICV infusion of a 10.0 micrograms dose of NPY enhanced significantly both rate of eating and total cumulative intake of flavored food in comparison to that after a similar infusion of NPY1-27 or either control solution. These results suggest that native NPY acting centrally affects gustatory and/or olfactory systems to a much greater degree than does NPY1-27.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sedative and motor-impairing effects of neuropeptide Y and ethanol in selectively bred P and NP rats

Past findings suggest a positive association between endogenous neuropeptide Y (NPY) activity and ethanol-induced sedation, and there is evidence for additive effects of administered NPY with sedative-hypnotics. The present investigation examined the effects of intracerebroventricular NPY injection on ethanol-induced sedation and motor impairment in selectively bred alcohol-preferring (P) and -nonpreferring (NP) rats. In Experiment 1, P and NP rats were assessed for loss and recovery of righting reflex (RR) following infusion with either NPY (10.0 microg) or aCSF followed by ethanol injection (2.5 g/kg ip). NPY reduced time to lose RR and increased time to regain RR similarly in P and NP rats. Blood-ethanol levels (BELs) were lower at time of recovery in NPY-treated rats relative to aCSF controls. Thus, NPY enhanced ethanol-induced sedation. In Experiment 2, P and NP rats pretreated with either saline or ethanol (1.0 g/kg ip) were assessed for motor activity following infusion with either NPY (2.5, 5.0, or 10.0 microg) or aCSF. Ethanol alone and NPY alone suppressed motor activity, but there were no additive effects between the two. Taken together, these results provide partial support for past observations of additivity between NPY and drug-induced sedation, and suggest a role for NPY in the neurobehavioral effects of acute ethanol exposure.     

Sensitized effects of neuropeptide Y on multiple ingestive behaviors in P rats following ethanol abstinence

Neuropeptide Y (NPY) suppresses ethanol drinking in alcohol-preferring (P) rats, an effect which is augmented following a single ethanol abstinence period. The present experiment tests both ethanol drinking and feeding in P rats following multiple abstinence periods. Female P rats had continuous access to 15% (v/v) ethanol and water for 6 weeks followed by 3 ethanol access cycles of 2 weeks with no ethanol and 2 weeks with ethanol. Following intracerebroventricular cannula implantation during the third period of ethanol abstinence, groups (n=12-13/dose) were infused with NPY (2.5, 5.0, 10.0 microg) or aCSF prior to ethanol reinstatement. Two additional groups (n=11-12/dose) were treated similarly except that ethanol access was uninterrupted, and they were infused with a single NPY dose (10.0 microg) or aCSF. NPY increased food intake in all groups, and this effect was greater following ethanol abstinence. NPY suppressed ethanol intake, and this suppression lasted longer (24 h post-infusion) in rats with a history of ethanol abstinence periods than rats with a history of continuous ethanol access (4 h post-infusion). These results confirm past findings and indicate that global dysregulation of brain NPY systems during ethanol abstinence may render P rats more sensitive to the behavioral effects of NPY.     

Milk consumption during adolescence decreases alcohol drinking in adulthood

Early onset of alcohol consumption increases the risk for the development of dependence. Whether adolescent consumption of other highly palatable solutions may also affect alcohol drinking in adulthood is not known. The purpose of this study was to determine the effects of adolescent consumption of four solutions: water, sucrose, sucrose-milk and milk on ethanol drinking in adult rats. Rats had limited access to one of the four solutions from day PND 29 to PND 51 and were subsequently trained to consume ethanol (E) using a sucrose (S) fade-out procedure. Adolescent consumption of sucrose and sucrose-milk solutions increased intake of 2.5% E when it was combined with 10% S but it had no effect on the drinking of 10% E alone. Adolescent consumption of milk and sucrose-milk significantly decreased the intake of 10% E when it was combined with 10% S, and milk significantly reduced 10% E consumption alone and when it was combined with 5% S. Adolescent exposure to the sucrose-milk and sucrose solutions was also found to increase sucrose and sucrose-milk consumption. Our findings suggest adolescent exposure to sucrose increases, whereas, exposure to milk reduces ethanol consumption in adult rats. Our results may provide a new theoretical approach to the early prevention of alcoholism.     

A typical Y1 receptor regulates feeding behaviors: effects of a potent and selective Y1 antagonist, J-115814

Neuropeptide Y (NPY) is a potent feeding stimulant. The orexigenic effect of NPY might be caused in part by the action of Y1 receptors. However, the existence of multiple NPY receptors including a possible novel feeding receptor has made it difficult to determine the relative importance of the Y1 receptor in feeding regulation. Herein we certified that the Y1 receptor is a major feeding receptor of NPY by using the potent and selective Y1 antagonist (-)-2-[1-(3-chloro-5-isopropyloxycarbonylaminophenyl)ethylamino]-6-[2-(5-ethyl-4-methyl-1,3-thiazol-2-yl)ethyl]-4-morpholinopyridine (J-115814) and Y1 receptor-deficient (Y1-/-) mice. J-115814 displaced (125)I-peptide YY binding to cell membranes expressing cloned human, rat, and murine Y(1) receptors with K(i) values of 1.4, 1.8, and 1.9 nM, respectively, and inhibited NPY (10 nM)-induced increases in intracellular calcium levels via human Y1 receptors (IC(50) = 6.8 nM). In contrast, J-115814 showed low affinities for human Y2 (K(i) > 10 microM), Y4 (K(i) = 640 nM) and Y5 receptors (K(i) = 6000 nM). Intracerebroventricular (ICV) (10-100 microg) and intravenous (IV) (0.3-30 mg/kg) administration of J-115814 significantly and dose-dependently suppressed feeding induced by ICV NPY (5 microg) in satiated Sprague-Dawley rats. Intraperitoneal (IP) administration of J-115814 (3-30 mg/kg) significantly attenuated spontaneous feeding in db/db and C57BL6 mice. Feeding induced by ICV NPY (5 microg) was unaffected by IP-injected J-115814 (30 mg/kg) in Y1-/- mice and was suppressed in wild-type and Y5-/- mice. These findings clearly suggest that J-115814 inhibits feeding behaviors through the inhibition of the typical Y1 receptor. We conclude that the Y1 receptor plays a key role in regulating food intake.     

Activation of the immune system in rats with lipopolysaccharide reduces voluntary sucrose intake but not intraoral intake

Traditional intake measures of voluntary consumption of food or fluid from a specific location involve both appetitive and consummatory behaviors. Appetitive behaviors are food finding behaviors displayed by an animal prior to the consumption of the food, whereas consummatory behaviors are the behaviors involved in the actual consumption of the food. Intraoral intake of a fluid can be measured by directly infusing it into the oral cavity of an animal and quantifying the consummatory behaviors. The present study compared the effects of immune activation (lipopolysaccharide, LPS) and toxin (lithium chloride, LiCl)-induced changes on both a traditional intake measure (bottle drinking) and an intraoral intake measure. In Experiment 1, rats were injected intraperitoneally with LPS (200 microg/kg), LiCl (0.15 M, 20 ml/kg) or NaCl vehicle, and voluntary sucrose (0.3 M) intake was monitored for 1 h from a graduated drinking tube. Voluntary intake was again assessed on a second test day, 72 h later under the same conditions. In Experiment 2, a continuous intraoral infusion of sucrose (0.3 M) was given via intraoral cannulae following systemic injections of LPS, LiCl or NaCl vehicle on two different test days, 72 h apart. Rats injected with LiCl displayed reduced sucrose intake on both the voluntary intake measure and the intraoral intake measure relative to controls (P's<.05). The reduced intake observed was of greater magnitude on the second test day of both experiments, consistent with conditioning effects. In contrast, LPS reduced sucrose intake only when assessed with the traditional intake measure. Intraoral sucrose intake remained unchanged relative to controls. The present results provide further evidence that activation of the immune system has adverse effects on the appetitive phase of ingestion, whereas the consummatory aspects are unaffected.     

Are some of the effects of ethanol mediated through NPY?

 Central administration of neuropeptide Y (NPY) in low concentrations has been shown to produce anxiolysis and suppression of locomotor activity, a behavioral profile not dissimilar to that of ethanol. The present study was conducted to ascertain whether NPY and ethanol have similar electrophysiological profiles and to evaluate the combined actions of NPY and ethanol. Eighty-five Wistar rats were stereotaxically implanted with electrodes aimed at dorsal hippocampus, amygdala, and frontal cortex. Rats were administered NPY [or saline (SAL)] intracerebroventricularly (ICV) whereas the doses of alcohol (or SAL) were given intraperitoneally (IP). Two doses of alcohol (0.75, 1.5 g/kg) and two doses of NPY (1, 3 nmol) were given alone and in combination. Drug effects were assessed using event related potentials (ERP) recorded in response to an auditory ”oddball” plus noise paradigm between 30 and 40 min post-drug. Multivariate analyses of variance (MANOVA) revealed that NPY produced a significant decrease in the amplitude and increase in the latency of the N1 component in cortex and a decrease in the amplitude of the P3 component in amygdala, but no overall effects in hippocampus. Ethanol produced identical effects to NPY on the N1 and P3 components of the ERP in cortex and amygdala. Combined administration of EtOH and NPY (1 nmol) produced effects equivalent to those seen following the higher doses of NPY (3 nmol) or EtOH (1.5 g/kg). These studies demonstrate that NPY and ethanol have a similar electrophysiological profile. In addition, the combined administration of NPY and ethanol produced additive effects. Received: 23 December 1997 / Final version: 9 May 1998     

Effects of self-administered alcohol or sucrose preloads on subsequent consumption in the rat

OBJECTIVE: The initial drink of alcohol is often conceptualized as "priming" the individual for the following drinking bout. For the alcoholic, this priming effect has been considered a key for the loss of control that then occurs. Although there have been a few animal studies examining the effects of an investigator-administered ethanol preload on subsequent ethanol self-administration, the effects of a small self-administered oral preload on subsequent consumption have not been examined. METHOD: Adult, male rats, initiated to self-administer ethanol using the sucrose-substitution procedure, were given brief access periods to drink ethanol or water, 5 minutes prior to a second opportunity to press a lever for an additional 20-minute access to a 10% ethanol solution. A second group of rats were trained to press a lever to gain access to a 3% sucrose solution, and the effects of sucrose or water preloads were examined and compared with results in the ethanol group. Results: In the ethanol group, both the ethanol and water preload intakes increased as preload access time increased and were not different from each other. However, ethanol preloads at the longer access times (60 seconds and 120 seconds) decreased subsequent ethanol consumption and at the highest time also affected ethanol-seeking behavior. Equal volumes of water intake at these longer access times had no effects on subsequent ethanol consumption. In the sucrose group, sucrose preload intakes increased as access time increased, but water preload intakes did not. Neither sucrose nor water preloads had any effect on subsequent sucrose consumption. CONCLUSIONS: The data failed to find any priming effect of ethanol preloads in terms of increased subsequent ethanol consumption. It appears that a major factor in the regulation of ethanol intake for the rat in this training procedure is the postingestional effects of ethanol, because taste stimuli did not appear to be important. However, it appears that these ethanol postingestive stimuli are not identical to those involved in the regulation of sucrose consumption.     

Electrophysiological response to neuropeptide Y (NPY): in alcohol-naive preferring and non-preferring rats.

Electroencephalograms (EEGs) and event-related potentials (ERPs) to auditory stimuli were recorded following intracerebroventricular administration of neuropeptide Y (saline, NPY: 1.0, 3.0 nmol) in two lines of rats that have been genetically selected for alcohol preferring (P) or non-preferring (NP) behaviors. Previous studies have demonstrated that NPY has a distinct electrophysiological profile that is similar to that of ethanol. In outbred Wistar rats, both NPY and ethanol produced highly significant decreases in the amplitude and increases in the latency of the N1 component of the ERP to all three auditory stimuli. Because the N1 has been associated with attention, these data suggest that both NPY and alcohol may diminish attentional processes. In the present study, NPY-induced decreases in N1 amplitude were also found, but only to the frequently presented tone. This suggests that both P and NP rats may have attenuated responses to NPY's effects on attention/arousal. Like outbred Wistars, P and NP rats were also found to have significant NPY-induced increases in N1 latency in the cortex and hippocampus. However, in the amygdala, while P rats evidenced increases in N1 latency and decreases in N1 amplitudes, NP rats displayed the opposite effects. Spectral analysis revealed that NPY also produced differential EEG responses in P and NP rats. In previous studies in outbred Wistar rats NPY has been found to produce slowing of delta (1-2 Hz) frequencies at the 1-nmol dose and reductions in power, particularly in the higher frequencies in the amygdala, at the 3-nmol dose. This electrophysiological profile is not unlike what is seen following alcohol and benzodiazepines and is associated with anxiolysis. P rats were found to have this general pattern of EEG responses to NPY but attenuated suggesting that they may have reduced responses to electrophysiological measures of the anxiolytic effects of NPY. In contrast, NP rats had NPY-induced EEG effects in amygdala and frontal cortex that were opposite to those seen in P rats. These opposing responses to NPY tended to produce a "normalization" of the power differences that existed between the two rat lines at baseline. Taken together with previous findings that P rats have decreased NPY concentrations in limbic and frontal cortical sites, these data suggest that differences in the regulation of NPY neurons may contribute to the expression of behavioral preference for ethanol consumption in these rat lines.     

Effect of nociceptin on alcohol intake in alcohol-preferring rats

The present study investigated the effect of nociceptin (NC), the endogenous ligand of the opioid-like orphan receptor ORL1, on ethanol intake in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. Acute intracerebroventricular (ICV) injection of 250 or 500 ng/rat of NC, just before access to 10% ethanol (offered 2 h/day), significantly increased ethanol intake. Subchronic (7 days) ICV injection of 500 ng/rat of NC, given just before access to 10% ethanol (for 30 min/day), resulted in a progressive decrease in ethanol consumption. After the end of NC treatment, rats progressively recovered their usual ethanol intake. When NC, 500 or 1000 ng/rat, was tested versus the effect of ethanol in the place conditioning paradigm, NC significantly reduced the increase in time spent in the ethanol-paired compartment after conditioning. This finding suggests that NC reduces the rewarding properties of ethanol in msP rats; thus, they may respond to the acute NC administration by increasing their ethanol intake in an attempt to achieve the usual reinforcing effect of ethanol, whereas subchronic NC treatment may result in extinction of ethanol drinking. The results of the present study suggest that the brain NC mechanisms may represent an interesting target of pharmacological interventions for the treatment of alcoholism. Received: 11 August 1998/Final version: 15 October 1998     

Identification of potent and selective neuropeptide Y Y(1) receptor agonists with orexigenic activity in vivo

Neuropeptide Y (NPY) binds to a family of G-protein coupled receptors termed Y(1), Y(2), Y(3), Y(4), Y(5), and y(6). The use of various receptor subtype-selective agonists and antagonists has facilitated identification of the receptor subtypes responsible for mediating many of the biological effects of NPY. For example, the potent orexigenic activity of NPY is believed to be mediated by both the Y(1) and Y(5) receptor subtypes. Several selective Y(5) receptor agonists that stimulate food intake in rodents are available, but no selective Y(1) receptor agonist has been reported. We have identified several NPY analogs that bind the NPY Y(1) receptor with high affinity and exhibit full agonist activity, measured as inhibition of forskolin-stimulated cAMP production in cells expressing the cloned NPY Y(1) receptor. [D-Arg(25)]-NPY, [D-His(26)]-NPY, Des-AA(10--17)[Cys(7,21),Pro(34)]-NPY, Des-AA(11--18)[Cys(7,21),D-Lys(9)(Ac)]-NPY, Des-AA(11--18)[Cys(7,21),D-Lys(9)(Ac),Pro(34)]-NPY, Des-AA(11--18)[Cys(7,21),D-Lys(9)(Ac),D-His(26)]-NPY and Des-AA(11--18)[Cys(7,21),D-Lys(9)(Ac),D-His(26), Pro(34)]-NPY bind the NPY Y(1) receptor with K(i) values of 0.9 +/- 0.2, 2.0 +/- 0.3, 0.2 +/- 0.05, 0.7 +/- 0.1, 0.2 +/- 0.01, 2.2 +/- 0.3, and 1.2 +/- 0.3 nM, respectively, and inhibit forskolin-stimulated cAMP production with EC(50) values of 0.2 +/- 0.02, 0.5 +/- 0.04, 0.3 +/- 0.03, 0.5 +/- 0.05, 0.4 +/- 0.16, 5.3 +/- 0.32, and 5.1 +/- 0.97 nM, respectively. These peptides are highly selective for the NPY Y(1) receptor relative to the NPY Y(2), Y(4), and Y(5) receptors. [D-Arg(25)]-NPY, [D-His(26)]-NPY and Des-AA(11--18)[Cys(7,21), D-Lys(9)(Ac),D-His(26),Pro(34)]-NPY stimulate food intake dose-responsively in Long-Evans rats for at least 4 h after intracerebroventricular administration. Although the involvement of Y(1) receptors in several physiological activities, such as vasoconstriction and anxiolysis, remains to be investigated, adequate tools are now available.     

Effect of clonidine on sucrose intake and water intake varies as a function of dose, deprivation state, and duration of exposure

Lick frequency was monitored in five-minute intervals over a one-hour period in rats given access to 8% sucrose (Experiment 1) or water (Experiment 2). Prior to the session, the rats were administered either isotonic saline or clonidine (6.24, 12.5, or 25 micrograms/kg). In deprived rats (82%) clonidine led to a dose-related increase in consummatory behavior. Water intake in deprived rats was depressed by clonidine. In rats maintained on a free-feeding schedule, the higher clonidine doses led to a decrement in sucrose intake over the first 15 minutes of access; whereas the 6.25 micrograms/kg dose stimulated consummatory behavior, but only during the first five minutes of access. There were no reliable effects of clonidine on sucrose intake late in the access period for the free-feeding rats. Water intake in free-feeding rats tended to be enhanced by the low dose of clonidine, particularly late in the access period. In general, deprivation enhanced sucrose intake and depressed water intake and clonidine exaggerated both of these trends.     

Effects of neuropeptide Y on the discriminative stimulus and antinociceptive properties of morphine.

Previous research indicates that opioid receptor blockade diminishes the effects of neuropeptide Y (NPY) on feeding and memory. Conversely, NPY attenuates naloxone-precipitated morphine withdrawal. The present study evaluated the effects of NPY on the discriminative stimulus and antinociceptive effects produced by the prototypical mu opioid, morphine. Rats were trained to discriminate 5.6 mg/kg morphine (IP) from saline using a standard two-lever, food-reinforced, drug discrimination procedure. Across a range of doses (3.0, 5.0, and 10 microg), intracerebroventricular (ICV) injection of NPY failed to substitute for, antagonize, or potentiate the discriminative stimulus effects of morphine. A warm-water tail-withdrawal procedure was used to examine the antinociceptive effects of morphine and NPY, alone and in combination. NPY (3.0 and 10 microg, ICV) failed to alter tail-withdrawal latencies from 52 degrees and 56 degrees C water, whereas morphine (1.0-30 mg/kg, IP) produced a dose-related increase in latencies at both water temperatures. A 10-microg dose of NPY also failed to alter the antinociceptive effects of morphine. This study does not support the idea that the discriminative stimulus and antinociceptive effects of morphine are dependent on an NPYergic pathway.     

Ethanol-metrecal diets: I. Effects of different levels of ethanol-derived kilocalories on consumption of diet,body weight and grams of ethanol ingested

Three experiments investigated the relationship between ethanol consumption and the percentage ethanol-derived kilocalories contained in liquid diets. Rats were chronically maintained on diets where different concentrations of ethanol (10%, 12%, 14%) were added to Metrecal so that 41%, 49% and 57% of all kilocalories consumed were derived from ethanol. The ethanol-Metrecal diet served as the sole source of calories. Results demonstrated that rats can be maintained fromextended time periods on diets where ethanol contributed approximately 50% of the daily kilocalories. Inspection of consummatory profiles revealed that an initial decrease occurred in volume of diet consumed when levels of ethanol were increased. This was followed by a gradual increase in the level of consumption until a new asymptotic level was established. Grams of ethanol/kg of body weight remained relatively constant over the range of ethanol concentrations employed. The results were discussed in respect to three factors controlling consummatory behavior-sensory stimuli, caloric intake and quantity of ethanol ingested.     

Alcohol drinking in the rat: Increases following intracerebroventricular treatment with tetrahydro-β-carbolines

Voluntary alcohol intake has been reported to increase in rats after the repeated intracerebroventricular (ICV) administration of 1,2,3,4-tetrahydro-β-carboline (THBC) and some tetrahydroisoquinolines, although negative results have also been reported. THBC is a normal constituent in human plasma and platelets; 1-methyl-1,2,3,4-tetrahydro-β-carboline (1-Me-THBC), however, occurs in the blood after a person drinks alcohol. We have evaluated the effects of two doses of THBC and 1-Me-THBC on voluntary alcohol consumption in rats. ICV infusions were given with Alzet® minipumps for 14 days rather than giving repeated ICV injections. Stability of the drugs in the pump was verified using mass spectrometry. On each day the rats chose between water, alcohol (increasing concentrations from 3 to 30%) and an empty bottle. Alcohol intake increased by about 100%(p<0.05) during the last six days when 47 nmoles/hr of either THBC or 1-Me-THBC was infused. At the end of the experiment elevated blood concentrations of alcohol (0.02–0.78%) were found in rats belonging to the THBC or 1-Me-THBC groups and drinking 30% alcohol. The infusion of 0.47 nmoles/hr of either drug did not increase alcohol intake as compared to control.     

Erucine suppresses ethanol intake and preference in alcohol-preferring Fawn-Hooded rats

Aim： Brucine （BRU） extracted from the seeds of Strychnos nux-vomica L is glycine receptor antagonist. We hypothesize that BRU may modify alcohol consumption by acting at glycine receptors, and evaluated the pharmacodynamic profiles and adverse effects of BRU in rat models of alcohol abuse. Methods： Alcohol-preferring Fawn-Hooded （FH/Wjd） rats were administered BRU （10, 20 or 30 mg/kg, sc）. The effects of BRU on alcohol consumption were examined in ethanol 2-bottle-choice drinking paradigm, ethanol/sucrose operant self-administration paradigm and 5-d ethanol deprivation test. In addition, open field test was used to assess the general locomotor activity of FH/Wjd rats, and conditioned place preference （CPP） was conducted to assess conditioned reinforcing effect. Results： In ethanol 2-bottle-choice drinking paradigm, treatment with BRU for 10 consecutive days dose-dependently decreased the ethanol intake associated with a compensatory increase of water intake, but unchanged the daily total fluid intake and body weight. In ethanol/sucrose operant self-administration paradigms, BRU （30 mg/kg） administered before each testing session significantly decreased the number of lever presses for ethanol and the ethanol intake, without affecting the number of sucrose （10%） responses, total sucrose intake, and the number of lever presses for water. Acute treatment with BRU （30 mg/kg） completely suppressed the deprivation-induced elevation of ethanol consumption. Treatment with BRU （10, 20, and 30 mg/kg） did not alter locomotion of FH/Wjd rats, nor did it produce place preference or aversion. Conclusion： BRU selectively decreases ethanol consumption with minimal adverse effects. Therefore, BRU may represent a new pharmacotherapy for alcoholism.